1. Field of the Invention
This invention refers to a process for the production of cephem, carba(dethia)cephem, and oxa(dethia)cephem compounds, and to 3-(fluorosulfonyl)oxy substituted cephem, oxacephem and carbacephem intermediates useful in this process.
2. Description of Related Art
Hoshi et al., U.S. Pat. No. 4,520,022 (May 28, 1985), discloses cephalosporin antibiotics having the 1-propenyl group in the 3-position which are represented by the following formula in which R.sup.1 and R.sup.2 are H, OH, OCH.sub.3, or Cl. ##STR1##
The 1-propenyl group of the Hoshi et al. compounds is preferably in the (Z) configuration because of enhanced antibacterial activity compared to the (E) configuration. These compounds are produced by reacting a 3-halomethyl cephalosporin with a triarylphosphine to yield a phosphoranyl intermediate which is then treated with an aldehyde to form the propenyl or substituted propenyl group.
The foregoing process affords a mixture of the cis(Z)- and trans(E)-isomers which requires costly separation or adjustment of process conditions to obtain the preferred, more antibacterially active cis(Z)-isomer. The overall yield of desired cis(Z)-isomer based on starting material is thus reduced by the amount of the trans(E)-isomer produced.
More recently palladium catalyzed coupling methods have been applied to the formation of alkenyl substituents at the 3-position of the cephalosporin nucleus in order to avoid formation of the undesired isomer and to improve yields. Allylic coupling of 3-halomethylcephems with vinyl stannanes under the influence of Pd(0) compounds, metal halides, and tris-(2-furyl)phosphine led to the production of novel cephalosporins (S. R. Baker et al. U.S. Pat. No. 4,847,373 patented Jul. 11, 1989). The method of W. J. Scott et al., J. Amer. Chem. Soc., 106, 4630-4632 (1984) for the Pd(0) compound/LiCl catalyzed coupling of a cyclohexenyl triflate with vinyl tributylstannane has been adapted to the reaction of a 3-trifloxyceph-3-em with (Z)-1-propenyl tributylstannane to produce various 3-((Z)-l-propenyl)ceph-3-ems (S. R. Baker et al., U.S. Pat. No. 4,870,168 patented Sep. 26, 1989).
Further research on the reaction scope and optimization of reaction conditions for the palladium catalyzed coupling of vinyl triflates and vinyl stannanes has been reported in Scott and Stille, J. Amer. Chem. Soc. 108, 3033- 3040 (1986), and Stille and Groh, J. Amer. Chem. Soc. 109, 813- 817 (1987) .
The coupling of a 3-trifloxyceph-3-em with an organic tributylstannane reagent in the presence of PdCl.sub.2 (CH.sub.3 CN).sub.2 without the aid of the phosphine reagent or LiCl required in the W. J. Scott et al. method (op. cit.) was reported by G. K. Cook and J. H. McDonald III at the 196th American Chemical Society National Meeting, Los Angles, Calif. Sep. 25-30, 1988, Division of Organic Chemistry, Abstract No. 32.